OBJECTIVES: To develop a cost-effectiveness analysis of a multidisciplinary support program (MSP) versus the conventional approach in the Hepatitis C (HC) treatment. METHODS: A total of 278 mono-infected naive HC patients were included: 131 in the MSP group and 147 patients were conventionally controlled (control group). All patients were treated with Peg-IFN-alfa-2a/ribavirin. The MSP team not only included hepatologists and nurses, but also, pharmacists, psychologists and assistants. Standard patient education, open and flexible visits scheduling, continued psychiatric evaluation and active medication control were carried out in the MSP. Treatment adherence, sustained virological response (SVR), and health resources use were evaluated. A Markov model for a lifetime horizon with seven health states and from the Spanish NHS perspective was developed. Transition probabilities and health states utilities were obtained from published literature. Costs were obtained from the Catalogue of Medicinal Products and from Spanish studies and databases (€-2010). 3.5% annual discount for costs and outcomes was applied. RESULTS: In the MSP group treatment compliance was higher than in the control group (94.6% vs 78.9%, p=0.0001). SVR was higher in the MSP group than in controls for all genotypes (77.1% vs. 61.9%, p=0.006), G-1/4 (67.7% vs 48.9%, p=0.02), and G-2/3 (87.7% vs. 81.4%, NS). For all genotypes, the cost per patient (including cost of drugs, health professionals and disease long-term complications) was €13,319 in MSP group and €16,184 in control group, furthermore, MSP group resulted more QALYs than controls (16.317 vs. 15.814), being MSP dominant (more effective, with lower costs) compared with the conventional approach. The MSP program was also dominant in G-1/4 patients (saving €2476, increasing 0.622 QALYs/patient) and G-2/3 (saving €1417, gaining 0.208 QALYs/patient). Results were stable for 95% CI of drug doses. CONCLUSIONS: HC treatment with Peg-IFN-alfa-2a/ribavirin in a MSP improves the compliance and is a cost-effective strategy compared with the conventional approach.